LIVER-FAILURE INDUCES A SYSTEMIC INFLAMMATORY RESPONSE - PREVENTION BY RECOMBINANT N-TERMINAL BACTERICIDAL PERMEABILITY-INCREASING PROTEIN

The observed increased susceptibility of patients with fulminant hepat ic failure for local and systemic infections has been hypothesized to be due to a failure of the hepatic clearance function and subsequent l eaking of endogenous endotoxins into the systemic circulation. However , experimental evidence of such a systemic inflammation during liver f ailure due to endogenous endotoxemia is lacking. Therefore, we designe d a study to clarify whether circulating endotoxins due to liver failu re cold lead to the development of systemic inflammation. In a rat mod el for liver failure induced by a two-thirds partial hepatectomy, we e valuated the course of circulating tumor necrosis factor and interleuk in-6, changes in blood chemistry and hemodynamics, and histopathologic al changes in the lungs. Partially hepatectomized animals, but not sha m-operated animals, demonstrated cardiac failure, increased levels of creatinin and urea, metabolic acidosis, high plasma levels of tumor ne crosis factor and interleukin-6, and an influx of PMNs in the lungs-to gether indicating the development of a systemic inflammatory response. Continuous infusion of recombinant N-terminal bactericidal/permeabili ty-increasing protein (rBPI(23)), a well described endotoxin-neutraliz ing protein, prevented these inflammatory reactions. Ex vivo experimen ts with rat plasma samples confirmed the presence of circulating endot oxins in partially hepatectomized rats as opposed to those treated wit h rBPI(23). Thus, our results indicate that the early phase of liver f ailure induces a systemic inflammatory response triggered by circulati ng endotoxins, which can be prevented by perioperative infusion of rBP I(23).